Microparticulate carrier systems are increasingly attracting attention for use in the parenteral delivery of therapeutic and diagnostics agents. A plethora of microparticle technology systems and chemistries has been proffered as vehicles to deliver agents subcutaneously, intravenously and intra-arterially. There are several key aspects to the "ideal vehicle". These include size, size distribution, payload, rate of biodegradation, ease of use, release kinetics and scalable reproducible production. Individual aspects of this "ideal vehicle" have been successfully addressed by others, notably drug payload, rate of biodegradation and, in part, size and size distribution.
Known vehicles have been manufactured by various techniques, largely solvent and emulsion-based. A disadvantage of these methods is that control of the key elements of the vehicle was attempted within one or two steps of the production. Thus, size, size distribution, payload and rate of biodegradation were all imparted on the product in a single, dynamic environment, typified by single and double emulsion systems or solvent evaporation techniques. Typically, for emulsion processes, the solution of drug, polymer and surface-modifying agents has been mixed with an insoluble solvent, emulsified, heated or stabilised to fix the particles, and then cleansed to remove oils or solvent incompatible with parenteral use.
The reaction vessel in emulsion or solvent evaporation systems is a principal characteristic of the prior art techniques. Within this vessel, the control of the microparticle morphology is achieved by balancing the interfacial forces of oil and water components, the interaction of solute at the interface, the balance between agitation, heat and shell formation and, of course, the incorporation of active within the polymer matrix. However, such technologies are largely incompatible with large-scale pharmaceutical manufacture required for a parenteral agent.
Almost without exception, the control of size and size distribution of known microparticles was vastly inferior to the size control attained by the spray-drying techniques described in the PCT publications WO-A-9112823, WO-A-9218164 and WO-A-9408627, in the production of microparticles for use in echo-contrast imaging and other potential parenteral uses. The acute toxicity of intravenous microparticles is largely associated with capillary blockage in the pulmonary circulation, concurrent decrease in the pulmonary venous pressure and loss of compliance. The relationship between particle size and LD toxicity is well recorded. Our own data show the precipitous elevation in toxicity of iv particles, with a mean size in excess of 6 .mu.m, the notional capillary size in lung tissue for non-deformable microcapsules.
Typically, the larger the mean size of the capsules, the significantly broader their size distribution, and the range of microparticle sizes can span two orders of magnitude. For therapeutic use, such as chemo-embolisation, the prospect of injecting a microparticle preparation containing particles ranging in size from 5-100 .mu.m is largely inconsistent with the concept of highly regionalised targeted delivery. At the upper end, there is the prospect of embolising major vessels up to and above 100 .mu.m in diameter, with the attendant risk of necrosing large perfusion territories; at the smaller end of the range, what essentially amounts to systemic distribution becomes possible.
The mechanism by which sustained release has previously been most commonly achieved in microparticle systems has been the control of matrix erosion and release to the surrounding medium of embedded or imbibed active agents. The active agents have either been incorporated at the time of particle production or imbibed into the matrix following fixation or stabilisation.
The incorporation of drugs into the matrix of the known microcapsules required heating in the presence of water and, inevitably, oxygen. This would almost certainly lead to adulteration of the drug by oxidative damage or uncontrolled cross-linking to the vehicle. In those cases where chemical stabilisation is used, the potential loss of active would be even worse.
Another mechanism of slowing or modifying release rates of drugs from soluble polymeric carriers has been to link the active agents via covalent linkages to the soluble polymer. In general, this has not been applied to microparticulate systems where drugs, ligands or antibodies are linked to particulate carriers.
The main impediment to linking active agents to prior art microparticles, is the latter's relative hydrophobicity. Since many of the chemical reactions required to achieve linkage are carried out in aqueous medium, such hydrophobic microparticles are almost impossible to derivatise. Where previous workers have produced hydrophilic microcapsules, they required complex formation in the presence of hydrophilic polymer, in an emulsion process.
The rate of biodegradation of microcapsules is determined largely by the extent of cross-linking. In the prior art systems, changes in cross-linking have detrimental effects upon drug loading and the ability subsequently to formulate the microparticles. Little effort was expended in attempting to manipulate this parameter to control the rate of biodegradation and drug release.
Microparticles of the prior art have required significant amounts of surfactants or sonication to achieve monodispersed suspension in aqueous media. Even when reconstituted, the microparticles have a propensity to agglomerate and are thus difficult to administer through hypodermic syringes.
It is known to use carrier materials in order to target cytotoxic drugs to the site of action. Typically, microparticles or other such materials comprise a matrix in which the drug is entrapped.